NK1 receptors (neuropeptide receptors of Substance P and tachykinins), are widely distributed in the organism's cells. Their presence has been verified in the central and peripheral nervous system of mammals, in the digestive apparatus, in the circulatory system, in haematopoietic and inflammatory and/or immune response cell lines cells, as well as in soft tissues and especially in vascular endothelium. Numerous biological processes are currently known in which regulation NK1 receptors are involved.
Substance P (SP), is the preferred agonist of the NK1 receptor, it is a undecapeptide produced naturally in mammals, it belongs to tachykinin family and its sequence was described by Veber et al. (U.S. Pat. No. 4,680,283). The tachykinin family also includes other peptides such as Neurokinin A, Neurokinin B, Neuropeptide K, Neuropeptide Gamma and Hemokinin I, among others.
The scientific bibliography has widely referred to the involvement of SP and other tachykinins in the aetiopathogenesis of various diseases of the human nervous system such as Alzheimer's Disease, Multiple Sclerosis, Parkinson's Disease, anxiety and depression (Barker et al., 1996. Neurosci. Res. 7, 187-214; Kramer et al., 1998. Science 11; 281(5383), 1640-5). The involvement of tachykinins has also been verified in the etiopathogenesis of various diseases such as rheumatoid arthritis, asthma, allergic rhinitis, inflammatory intestinal diseases such as ulcerative colitis and Crohn's disease (Maggi et al., 1993. Journal of Autonomic Pharmacology 13, 23-93).
In this sense, non-peptide NK1 receptor antagonists have been developed as medicaments for the treatment of various central nervous system disorders such as depression, psychosis and anxiety (WO 95/16679, WO 95/18124, WO 95/23798 and WO 01/77100). It has been disclosed that the use of selective NK1 receptor antagonists is useful in the treatment of nauseas and vomiting induced by antineoplastic chemotherapies and in the treatment of certain forms of urinary incontinence (Quartara et al., 1998. Neuropeptides 32(1), 1-49; Doi et al., 1999. Eur. J. Pharmacol. 383(3), 297-303).
In a work published in 2003 (Giardina et al., 2003. IDrugs 6(8), 758-72.), a review was made of the more recent patents on NK1 receptor antagonists. The molecules of the most important global manufacturers are described with indication of their possible applications, among which we can highlight: anti-depressive, anti-inflammatory, anxiolytic, antiemetic, treatment of ulcerative colitis and others.
It has been demonstrated that NK1 and SP receptor antagonists may inhibit the proliferation of lung cancer cells (Orosz et al., 1995. Int. J. Cancer 60(1), 82-7, Bunn et al., 1994. Cancer Res. 54(13), 3602-10), brain tumours (Palma et al., 2000. Life Sci. 67(9), 985-1001), APUDOMAS (enterochromaffin cell tumours; patent EP 773026), prostate cancers (patent WO 2001001922), stomach and colon cancers (Rosso et al., 2008. Tumour Biol. 29(4), 245-54), melanoma (Munoz et al., 2010. Lab. Invest. 90(8), 1259-69).
Various studies with specific antagonists of neurokinin NK receptors such as CP-96341-1 (Pfizer), MEN 11467, SR 48968 (Sanofi) and MEN 11420 (Nepadutant) have demonstrated the efficacy thereof in blocking cell proliferation (Singh et al., 2000. Proc. Natl. Acad. Sci. 97(1), 388-93; and Bigioni et al., 2005. Anticancer Drugs 16(10), 1083-9.).
Patent ES 2246687 claims the use of non-peptide NK1 and SP receptor antagonists in the preparation of a pharmaceutical composition for the production of apoptosis in tumour cells of mammals.
In the genesis and development of cancer there is not just the intervention of molecular mechanisms typical of tumour cells, but the cells surrounding the tumour have great importance (specifically stroma cells and inflammatory cells), as well as the interactions that take place between the tumour cells and these cells surrounding the tumour (McAllister et al., 2010. J. Clin. Oncol. 28(26), 4022-8; Ikushima et al., 2010. Nat. Rev. Cancer 10(6), 415-24). In this sense, it has been published that some substances, e.g. nuclear factor NF-KB (nuclear factor kappa B), SPARC (secreted protein acidic, cysteine-rich), TGF-α and TGFβ (transforming growth factors α and β, respectively) or Metalloproteinase (MMPs), are present in the tumour microenvironment and are of great importance in the genesis and progression of tumours (Coussens et al., 2002. Nature 19-26; 420(6917), 860-7; Berzofsky et al., 2004. J. Clin. Invest. 113, 1515-1525; Carmeliet et al., 2000. Nature September 14; 407(6801), 249-57; Hanahan et al., 2000. Cell January 7; 100(1), 57-70).
It is known that the cells surrounding the tumour (specifically the stroma cells and inflammatory cells) express a large amount of the NK1 receptor and that NK1 receptor antagonists modulate the production of these substances by the cells surrounding the cancerous tumours, preventing the survival and progression of these tumours (patent PCT/ES2012/070865).
Therefore, and in conclusion, nowadays the following facts are known in the state of the art:                1. That NK1 receptors are widely disseminated in the human organism.        2. That tachykinins and, in particular, SP act on the NK1 receptors.        3. That the use of non-peptide NK1 receptor antagonists is possible for the preparation of a medicament for the treatment of various central nervous system disorders such as depression, psychosis and anxiety which have been object of claim in various patent applications (WO 95/16679, WO 95/18124, WO 95/23798 and WO 01/77100).        4. That the use of non-peptide NK1 receptor antagonists has demonstrated effects on tumour cells, which results in their cell death by apoptosis (ES 2246687) in in vitro tumour cell cultures.        5. That, as it has been mentioned, patent ES 2 246 687 claims the use of non-peptide NK1 receptor antagonists to induce death and apoptosis in tumour cells (and it lists specifically a number thereof). Therefore, it does not include the effects that non-peptide NK1 receptor antagonists may perform at a level of substances and cells that compose the tumour microenvironment, which are of vital importance for the genesis, development and progression of tumours.        6. The presence of NK1 receptors has been demonstrated in blood cells involved in the inflammatory and/or immune response, in cells of the stromal matrix and in the vascularization cells that surround tumour cells. It is known that stromal cells, blood cells involved in the inflammatory and/or immune response and the vascularization cells, influence the evolution of malignant tumours.        7. It has been demonstrated that NK1 receptor antagonists may prevent the survival and progression of tumours by means of modulating the functioning of the microenvironment cells.        
However, the known precedents, which include the use of non-peptide NK1 receptor antagonists to cause death (apoptosis) in tumour cells and the modification of the peritumoral environment by means of the induction of changes in the cells forming said environment and in the substances secreted by them, with the aim of preventing or hindering the genesis, development or progression of tumours, at present, there is controversy about the effect of the in vivo use of NK1 receptor antagonists for the treatment of cancerous tumour disease (Harford-Wrigth et al., Drug Discovery, 2013, 8, 13-23). In this sense, the data published in vivo are contradictory (Palma C, et al., Br J Cancer 2000; 82: 480-7; Bigioni M, et al. Anticancer Drugs 2005, 16, 1083-9), so that in some cases the use of NK1 receptor antagonists (such as Aprepitant) cause reduction in the tumour size in experimental animal models (in vivo) and in other cases does not produce them. In particular, in a recently published work, the use of Aprepitant at doses of 3 mg per kilogram of weight and day, does not cause a reduction in brain tumour sizes in animal experimentation models in mice (Lewis K M, et al., Anti-Cancer Drugs 2013, 24, 344-354).
Therefore, the efficacy of Aprepitant as treatment of cancerous tumours in animals (including human beings) is not a “universal” effect but dependent on dose and tumour type.
Thus, the object of the present invention and the technical advantage it provides, is the use of non-peptide NK1 receptor antagonists for the treatment of cancer, in a predetermined dose range, for the manufacturing of a medicament or pharmaceutical composition, by suitable administration route and at suitable doses, of use in the therapeutic treatment of cancer by direct administration to a mammal, including humans.
The fact that the invention influences cancer treatment through the use of suitable doses to reduce tumour sizes, prevent their development and, possibly, induce their disappearance, makes it possible to adjust the effective doses of anti-tumour agents both based on chemotherapy and radiotherapy, and the nature of the combinations to be performed therewith. This entails a more effective treatment, with a broader spectrum in treatable tumours, at possibly more adjusted doses, which involves less associated secondary effects and better quality of life for the patients during and after treatment.